The invention relates generally to a process for coating medical devices, particularly surgical devices such as stents. More specifically this invention relates to an improved process for coating stents and the like using super-critical carbon dioxide.
Stents, which are generally open tubular structures, have become increasingly important in medical procedures to restore the function of body lumens. Stents are now commonly used in translumenial procedures such as angioplasty to restore an adequate blood flow to the heart. However, stents may stimulate foreign body reactions that result in thrombosis or restenosis. To avoid these complications a variety of polymeric stent coatings and compositions have been proposed in the literature both to reduce the incidence of these or other complications or by delivering therapeutic compounds such as thrombolytics to the lumen to prevent thrombosis or restenosis. For example stents coated with polymers containing thrombolytics such as heparin have been proposed in the literature.
Stents generally are coated by simple dip or spray coating of the stent with polymer or polymer and a pharmaceutical/therapeutic agent or drug. These methods were acceptable for early stent designs that were of open construction fabricated from wires (Wiktor stent) or from ribbons (Gianturco). Dip coating with relatively low coating weights (about 4% polymer) could successfully coat such stents without any problems such as excess coating bridging (i.e. forming a film across) the open space between structural members of the device. This bridging is of particular concern when coating more modern stents that are of less open construction, such as the Palmaz-Schatz, Crown, Multilink or GFX stents. Bridging of the open space (slots) is undesirable because it can interfere with the mechanical performance of the stent, such as expansion during deployment in a vessel lumen. Bridges may rupture upon expansion and provide sites that activate platelet deposition by creating flow disturbances in the adjacent hemodynamic environment or pieces of the bridging film may break off and cause further complications. Bridging of the open slots may also prevent endothelial cell migration complicating the endothelial cell encapsulation of the stent.
Similarly, spray coating can be problematic in that there is a significant amount of spray lost during the process and many of the pharmaceutical agents that one would like to incorporate in the device are quite costly. In addition, in some cases it would be desirable to provide coated stents with high levels of coating and drug. High concentration coatings (xcx9c15% polymer with additional drug) are the preferred means to achieve high drug loading. Multiple dip-coating has been described in the literature as a means to build thicker coatings on the stent. However, composition and phase dispersion of the pharmaceutical agents affect sustained release profile of the pharmaceutical agent. In addition, the application of multiple dip coats from low concentration solutions often has the effect of reaching a limiting loading level as an equilibrium is reached between the solution concentration and the amount of coating, with or without pharmaceutical agent, deposited on the stent. Thus there is a continuing need for new and improved stent coating techniques.
At a thermodynamic state above the critical temperature and pressure, gases can exist as fluids which exhibit a number of unique properties. Supercritical fluids (SCF""s) are dense gases and liquids at conditions above their respective thermodynamic critical points. By operating in the critical region, pressure and temperature can be used to regulate density, thus regulating the solvent power of SCF""s. SCF""s exhibit high solvent power for many normally insoluble substances and as such have been used for industrial applications such as the extraction of specific substances from liquid and solid mixtures. For example, SCF""s have been used for decaffeination of coffee, removal of saturated fats and cholesterol from snacks and food products and other extraction processes, and to test the presence of pesticides in crops.
In addition to their use in extraction processes, SCF""s have recently been proposed for use in the deposition of thin films. U.S. Pat. No. 4,737,384 to Murthy et al. describes a process for depositing a thin metal or polymer coating on a substrate by exposing the substrate at supercritical temperatures and pressures to a solution containing the metal or polymer in a solvent and reducing the pressure or temperature to subcritical values to deposit a thin coating of the metal or polymer on the substrate. PCT application WO 99/19085 describes a method of preparing coatings of thin films onto particulate substances using SCF""s. Neither of these references however, disclose the use of SCF""s for the coating of stents or other medical devices.
The invention relates to a process for coating stents and other medical devices with a thin film polymer optionally containing a therapeutic agent, using a supercritical fluid deposition process. The process comprises the steps of:
(1) contacting the stent or other medical device with a liquid coating solution comprising a film forming biocompatible polymer and an optional therapeutic agent in a solvent under super critical temperature and pressure conditions such that the polymer and therapeutic agent are solubilized under the super critical conditions but insoluble under sub-critical conditions; and
(2) reducing the pressure and/or temperature conditions to sub-critical levels to deposit a thin film coating of said polymer and optional therapeutic agent on the stent or other medical device.
In another embodiment, the stent or other medical device is coated using super critical fluid as an anti-solvent. In this process, the polymer and optional drug combination is dissolved in suitable solvent and exposed to the stent or other medical device. The super critical fluid is then used to extract the solvent, thereby depositing a thin film of the polymer and optional drug on the surface of the stent or other medical device.
In still another embodiment of the invention, the stent or other medical device is coated with a drug and polymer by using a combination GAS/RESS procedure. This process comprises the steps of:
(a) contacting the stent or other medical device with a drug dissolved in a suitable solvent;
(b) removing the solvent by extracting the solvent under sub-critical or super critical conditions using a super critical fluid as an anti-solvent to dissolve the solvent from the drug solution, thus precipitating the drug on the surface of the stent or other medical device;
(c) contacting the stent or other medical device with a liquid coating solution comprising a film forming biocompatible polymer in a solvent under super critical temperature and pressure conditions such that the polymer is solubilized under the super critical conditions but insoluble under sub-critical conditions; and
(d) reducing the pressure and/or temperature conditions to sub-critical levels to deposit a thin film coating of said polymer on the stent or other medical device.
In another embodiment of the invention there is provided a stent or other medical device coated with a film forming biocompatible polymer and an optional therapeutic agent wherein the polymer and optional therapeutic agent are deposited on the stent or medical device using a super critical fluid nucleation process. The process of the invention provides a coated stent with an exceptionally smooth surface which is advantageous in preventing restenosis.
Through application of the preferred combination GAS/RESS procedure of the invention, the process yields a drug+polymer coated stent that has the potential advantage of minimizing the burst release of the drug since the process involves first coating the drug and then putting the polymer coat on top of it.
Several advantages resulting from the process of this invention are compared to conventional polymer dipping processes. For example, the process is environmentally friendly and does not require the use of toxic solvents and the process is fully contained so there is no exposure of the drugs to production personnel and the environment. The process can employ relatively inexpensive substances such as carbon dioxide which can be recycled.